Serum High-Mobility-Group Box 1 as a Biomarker and a Therapeutic Target during Respiratory Virus Infections

Abstract

Host-derived “danger-associated molecular patterns” (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases. There is accumulating evidence that generation of DAMPs such as oxidized phospholipids and high-mobility-group box 1 (HMGB1) during influenza virus infection leads to acute lung injury (ALI). Treatment of influenza virus-infected mice and cotton rats with the Toll-like receptor 4 (TLR4) antagonist Eritoran blocked DAMP accumulation and ameliorated influenza virus-induced ALI. However, changes in systemic HMGB1 kinetics during the course of influenza virus infection in animal models and humans have yet to establish an association of HMGB1 release with influenza virus infection. To this end, we used the cotton rat model that is permissive to nonadapted strains of influenza A and B viruses, respiratory syncytial virus (RSV), and human rhinoviruses (HRVs). Serum HMGB1 levels were measured by an enzyme-linked immunosorbent assay (ELISA) prior to infection until day 14 or 18 post-infection. Infection with either influenza A or B virus resulted in a robust increase in serum HMGB1 levels that decreased by days 14 to 18. Inoculation with the live attenuated vaccine FluMist resulted in HMGB1 levels that were significantly lower than those with infection with live influenza viruses. RSV and HRVs showed profiles of serum HMGB1 induction that were consistent with their replication and degree of lung pathology in cotton rats. We further showed that therapeutic treatment with Eritoran of cotton rats infected with influenza B virus significantly blunted serum HMGB1 levels and improved lung pathology, without inhibiting virus replication. These findings support the use of drugs that block HMGB1 to combat influenza virus-induced ALI.

Glycyrrhetinic acid alleviates hepatic inflammation injury in viral hepatitis disease via a HMGB1-TLR4 signaling pathway

“…If an excessive amount is produced, it will cause serious pathological damage [47]. During respiratory viral infection, serum HMGB1 acts as a biomarker and a therapeutic target [38]. However, in viral infection disease, the effect of HMGB1 on virus replication is multifactorial.…”

“…6H). TLR4 is one of downstream receptors of the HMGB1, but TLR4 mediates HMGB1 release in viral infection similar to its regulation in hepatic sterile inflammation disease [37,38].…”

Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

“…Considering that host DAMPs might play a central role in acute lung injury and are detected in the lungs of patients with severe IAV or SARS-CoV infections [ 49 , 50 ], an important relation regarding the current SARS-CoV-2 situation underlies this interaction. To date, the roles of TLRs in human diseases are still not fully understood, however, TLR4 has shown itself as an important feature in inflammatory diseases initiation and progression [ 51 ].…”

Serum high‐mobility group box 1 is associated with the onset and severity of acute exacerbation of idiopathic pulmonary fibrosis

“…demonstrated that HMGB1 itself can cause acute lung injury in mice . Air pollution and respiratory viral infection are potential triggers of AE‐IPF, and respiratory viral infection can lead to increased expression of HMGB1 both in lung epithelial cells and in circulation . These observations suggest that the excessive release of HMGB1 induced by secondary alveolar epithelial injury might have a role in the initiation of AE‐IPF.…”